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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study, meets generally accepted scientific principles of GLP, acceptable with restrictions

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980
Reference Type:
publication
Title:
Developmental Toxicity Studies of Caprolactam in the Rat and Rabbit.
Author:
Gad S.C. et al.
Year:
1987
Bibliographic source:
J. Appl. Toxicol. 7, 317-326
Reference Type:
publication
Title:
Rat and rabbit teratology studies of Caprolactam.
Author:
Gad, S.C. et al.
Year:
1984
Bibliographic source:
Proc. Symp. Ind. Approach Chem. Risk Assess. Caprolactam Relat. Compd. Case Study, 164-189.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Principles of method if other than guideline:
This study was designed to evaluate the developmental toxicity potential of Caprolactam in rats.
The test material was administered by oral intubation on days 6 through 15 of gestation to each of three groups of twenty pregnant female rats of the Fischer 344 strain at levels of 100, 500, and 1000 mg/kg bw, respectively. A fourth group of twenty pregnant rats received only the vehicle (distilled water) and served as the control group. Criteria evaluated for evidence of compound effect were maternal body weight and body weight changes, food consumption, clinical observations, survival, gross pathology, implantation and resorption efficiencies, and offspring viability and development.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Caprolactam
- Physical state: white crystalline solid
- Analytical purity: approximately 100 %

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Microbiological Associates, Walkerville, Maryland
- Weight at study initiation: 149-205 g
- Diet (e.g. ad libitum): Purina Laboratory Chow
- Water (e.g. ad libitum): Tap water
- Acclimation period: 20 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Appropriate amounts of the test material were dissolved in distilled water on a weight-per-volume basis and administered by oral intubation (amount based on individual body weight, dosing factor 10 ml/kg bw) from day 6 through day 15 of gestation.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6-15 of gestation
Frequency of treatment:
daily
Duration of test:
day 20 of gestation
No. of animals per sex per dose:
20
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during day 6-20 of gestation


BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 11, 15, and 20 of gestation


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: Yes on days 6, 11, 15, and 20 of gestation


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined:

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
- The maternal survival rate was statistically significantly lower in the high-dose group when compared with the control. Nine high-dose females (six pregnant, three not pregnant) were found dead during the treatment phase of this study.

- Clinical observations made during the treatment and post treatment periods that were noted in the treated groups: urine stains, a rough hair coat, a red discharge from the vagina, a bloody crust on or about the eyes, mouth, and/or nose, a thin and/or hunched appearance, and/or depression.

- The mean body weight values of the high dose group on day 15 and 20 of gestation and the mean body weight changes of the mid- and high dose groups for the days 6-11 and 6-15 were statistically significantly (p<0.05) lower than the control values at these intervals (Table 1). The percent body weight change in the mid dose group during the treatment period 6-11 and 6-15 were -0.8 and 5.2, respectively, in comparison to 6.2 and 13.4 in control group. Similarly in the high dose group, the percent body weight change were -2.7 and 2.3, respectively.

- The mean food consumption was significantly lower (p<0.05) in the mid- and high-dose groups.

- The pregnancy rates were slightly higher in the low- and mid-dose groups (80 and 75%) than in the control (60%). The mean implantation efficiencies were slightly lower in the low-and high-dose groups than in the control (Table 2). The mean incidence of resorptions was statistically significantly (p<0.05) higher than the control value in the high-dose group (Table 2).

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
- The mean incidence of fetal death was comparable for all groups, and the mean incidence of fetal viability was lower in the high-dose group than in the control group.
- The mean body weight of the male fetuses in the treated groups was slightly lower than that of the control group, and the mean body weight of the female fetuses in the mid-and high-dose groups was slightly lower than that of the control group. The difference in the mean body weight was remarkable only in the high dose males (10% low) and females (15% low), however the difference was not statistically significant.
- The mean fetal lengths were slightly lower (below 10 %) in the high dose-group than in the controls.
- No treatment-related visceral or skeletal anomalies were observed. Skeletal variants were observed in each group with the mid- and high dose groups having a higher incidence of skeletal variants than the control group. In the control group the variants included incomplete ossification of the skull (supraoccipital or interparietal), a nonfused vertebral column (centra), and/or extra ribs. The variants observed in the treated groups included incomplete ossification of the skull (supraoccipital and/or interparietal), incomplete and/or malfused sternebrae, extra ribs, and/or nonfused and/or incomplete ossification of the vertebral column (centra). No statistically significant differences were noted in these data.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Mean maternal body weights and body weight changesa

Body weights

Days

Dose level (mg/kg bw)

0

100

500

1000

 

 

Mean weight (g)

0

167.2

174.4

170.8

168.0

6

176.7

184.4

180.7

176.8

11

187.6

192.9

179.3

172.0

15

200.3

204.4

190.1

180.8s-

20

234.6

233.9

225.3

208.8s-

Mean change (g)

Pre-treatment period

0-6

9.5

10.5

9.9

8.8

Treatment period

6-11

10.9

8.0

-1.4s-

-4.8s-

Treatment period

11-15

12.7

11.5

10.8

8.8

Total Treatment period

6-15

23.6

19.5

9.4s-

4.0s-

Post-treatment period

15-20

34.3

29.5

35.2

28.0

Total study period

0-20

67.4

59.5

54.5

40.8

Percent change (%)

Pre-treatment period

0-6

5.7

6.0

5.8

5.2

Treatment period

6-11

6.2

4.3

-0.8

-2.7

Treatment period

11-15

6.8

6.0

6.0

5.1

Total Treatment period

6-15

13.4

10.5

5.2

2.3

Post-treatment period

15-20

17.1

14.4

18.5

15.5

Total study period

0-20

40.3

34.1

31.9

24.3

aOnly data from pregnant rats surviving to Day 20 of gestation were included in calculations of the mean values

S-:Statistically significantly (p<0.05) lower than the control value.

Table 2. Summary of the Ovarian, Uterine, and Litter Dataa

Parameters

Dose level (mg/kg bw)

0

100

500

1000

Number of females mated

20

20

20

20

Number of rats pregnant

12

16

15

11

Pregnancy rate (%)

30.0

80.0

75.0

55.0

Number of pregnant rats surving to day 20

12

16

15

5

Maternal survival rate (%)

100.0

100.0

100.0

45.5

Mean number of:

Corpora lutea

11.8

12.9

11.7

12.8

Implantations

9.6

8.5

9.6

8.6

Resorptions

0.4

0.5

0.3

3.2

Fetuses- Dead

0.0

0.0

0.0

0.0

Fetuses- Live

9.2

8.6

9.3

5.4

Indices calculated on aper litter per group basis:

Mean implantation efficiency (%)

81.78

70.56

81.11

67.92

Mean incidence of resorption (efficiency) (%)

4.64

5.24

3.27

41.34

Mean incidence of fetal death (%)

0.00

0.00

0.00

0.00

Mean incidence of fetal viability (%)

95.36

94.76

96.39

58.66

aOnly data from pregnant rats surviving to Day 20 of gestation were included in calculations of the mean values

S-:Statistically significantly (p<0.05) lower than the control value.

S+:Statistically significantly (p<0.05) higher than the control value.

Applicant's summary and conclusion